Glucosamine is a well-known amino monosaccharide found in chitin, glycoproteins and glycosaminoglycans. Unfortunately, pure glucosamine derivatives containing neither any halides (e.g., chloride, iodide, etc.) nor any cations (e.g., calcium, potassium, sodium, etc.) are not currently available. What is currently available in the marketplace is a glucosamine halide salt such as glucosamine hydrochloride or glucosamine hydroiodide or mixtures of salts together with glucosamine. Mixed salts of glucosamine hydrochloride and alkaline or earth alkaline metal sulfates or phosphates are well known. Such mixed salts are used rather than glucosamine phosphate alone since the latter is unstable in view of its highly hygroscopic nature and the facility with which its amino group oxidizes if not completely saltified, see, e.g., U.S. Pat. No. 4,642,340 and U.S. Pat. No. 3,683,076 which disclose mixtures of glucosamine phosphate and glucosamine hydroiodide.
In EP 0 214 642, free glucosamine base containing residual chloride is converted to a mixed salt of glucosamine phosphate and potassium chloride by dissolving the glucosamine base in water, adding a stoichiometric quantity of concentrated sulfuric acid to form a solution of glucosamine phosphate in water and dissolving a stoichiometric amount of potassium chloride in the solution. The mixed salt is precipitated from the solution by addition of a precipitant such as isopropanol, stirring the mixture for about 14 hours to complete the precipitation, cooling the reaction mass to 0° C. and recovering the precipitated salt by filtration. This process results in low yields.
Topically applied cosmetic and dermatologic formulations containing hydroxy-acids are well known in the prior art, e.g., see U.S. Pat. Nos. 2,118,566; 3,124,506; 3,666,863; 3,879,537; and the like
U.S. Patent Application 2004/0092482 A1 and U.S. Pat. No. 5,877,212 disclose the preparation of complexes of glucosamine and hydroxyacids and their use in topically applied cosmetic and dermatologic formulations. However, such compositions are disadvantageous since they contain a halide such as sodium or potassium chloride. This results from the fact that glucosamine is only available as the hydrochloride salt regardless of whether it is extracted from shellfish or manufactured by a fermentation process. When the glucosamine hydrochloride is neutralized with a base such as sodium or potassium hydroxide to release the glucosamine free base, the composition will necessarily also contain sodium or potassium chloride. Since both the free glucosamine base and the halide salt are both fully soluble in water, it has not been possible to prepare halide-free glucosamine base.
In co-pending patent application Ser. No. 11/223,336, filed Sep. 9, 2005 (corresponding to provisional patent application Ser. No. 60/611,709, filed Sep. 17, 2004), the disclosure of which is incorporated herein in its entirety by reference, a process is disclosed for converting a glucosamine halide salt into a halide-free glucosamine base. The resultant halide-free glucosamine base may then be used as is for those medicinal purposes in which the presence of a salt such as sodium or potassium chloride, sodium or potassium phosphate, sodium or potassium iodide, etc. is undesirable. The halide-free glucosamine base may also be employed to prepare a wide variety of useful derivatives such as glucosamine salts, e.g., glucosamine phosphate, glucosamine sulfate, n-acetyl-glucosamine, glucosamine salts of drugs having acidic functionalities, the glucosamine base-organic acid salts of the invention, etc., wherein such derivatives do not contain any objectionable halide or cations such as sodium or potassium.
The halide-free glucosamine base prepared by the process disclosed in the above-identified co-pending provisional application may be readily converted into a salt of the glucosamine base and an organic acid by the process described below. However, the resultant salt may be unstable—it may decompose when exposed to ambient temperatures and/or the atmosphere. Therefore, some of the glucosamine base-organic acid salts must be kept refrigerated in a closed container, thereby limiting the usefulness of the compositions.
It would be most desirable if a method could be found for stabilizing the halide-free glucosamine base-organic acid salts without having any adverse effect on the physical and chemical properties of the salts such that the salts could be exposed to the atmosphere and stored at ambient temperatures without decomposition occurring.